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Lung tumourigenesis in a conditional Cul4A transgenic mouse model
Author(s) -
Yang YiLin,
Hung MingSzu,
Wang Yang,
Ni Jian,
Mao JianHua,
Hsieh David,
Au Alfred,
Kumar Atul,
Quigley David,
Fang Li Tai,
Yeh CheChung,
Xu Zhidong,
Jablons David M,
You Liang
Publication year - 2014
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.4352
Subject(s) - biology , cullin , ubiquitin ligase , cancer research , ectopic expression , cell cycle , cell growth , microbiology and biotechnology , ubiquitin , cancer , cell culture , gene , genetics
Cullin4A ( Cul4A ) is a scaffold protein that assembles cullin– RING ubiquitin ligase ( E3 ) complexes and regulates many cellular events, including cell survival, development, growth and cell cycle control. Our previous study suggested that Cul4A is oncogenic in vitro , but its oncogenic role in vivo has not been studied. Here, we used a Cul4A transgenic mouse model to study the potential oncogenic role of Cul4A in lung tumour development . After Cul4A over‐expression was induced in the lungs for 32 weeks, atypical epithelial cells were observed. After 40 weeks, lung tumours were visible and were characterized as grade I or II adenocarcinomas. Immunohistochemistry ( IHC ) revealed decreased levels of Cul4A ‐associated proteins p21 CIP1 and tumour suppressor p19 ARF in the lung tumours, suggesting that Cul4A regulated their expression in these tumours. Increased levels of p27 KIP1 and p16 INK4a were also detected in these tumours. Moreover, the protein level of DNA replication licensing factor CDT1 was decreased. Genomic instability in the lung tumours was further analysed by the results from pericentrin protein expression and array comparative genomic hybridization analysis. Furthermore, knocking down Cul4A expression in lung cancer H2170 cells increased their sensitivity to the chemotherapy drug cisplatin in vitro , suggesting that Cul4A over‐expression is associated with cisplatin resistance in the cancer cells. Our findings indicate that Cul4A is oncogenic in vivo , and this Cul4A mouse model is a tool in understanding the mechanisms of Cul4A in human cancers and for testing experimental therapies targeting Cul4A . Published by John Wiley & Sons, Ltd